PROJECT SUMMARY (See InstnjcUons): The long-term objectives of this application are to understand and reduce the large numbers of pregnancies that are lost because of inappropriate regression of the primate corpus luteum (CL) at the end of the menstrual cycle, and to contribute to better management of cardiovascular disease (CVD) risk in wromen by determining how reproductive processes influence CVD risk factors. The research plan will address the novel hypothesis that cholesterol uptake and efflux activities, regulated by liver x receptor (LXR) a and/or p,determine luteal steroidogenic lifespan and reduce the risk of developing CVD. To test this hypothesis, the first aim will determine whether LXR signaling mediates prostaglandin F2a (PGF2a)-induced luteolysis in non-primate species. Sheep will receive either placebo or PGF2a during the mid-luteal phase with serial blood samples collected to verify reduced progesterone (P4) levels indicative of luteolysis. Corpora lutea will be collected at 12, 24, or 48 hours after injection and expression of known LXR target genes and lipoprotein receptors will be determined, as well as differences in cholesterol efflux and extracellular lipoprotein uptake in cell cultures derived from freshly isolated tissue. This will test the hypothesis that the LXRs mediate PGF2a-induced luteolysis, and will determine the utility of a PGF2a-induced luteolytic model for future studies on the functional importance of the LXRs in luteal function. The second specific aim will differentiate direct ovarian contributions from systemic estradiol (E2) and P4 effects on circulating lipids during the normal menstrual cycle and hormonal oral contraceptive cycles. Circulating lipid levels will be determined in healthy, premenopausal women during their normal menstrual cycle, after having ovarian activity temporarily stopped to mimic menopause, while receiving E2 and P4 replacement during induced menopause, and during a monophasic combined hormonal oral contraceptive cycle. This aim will better our understanding of the mechanisms underlying premenopausal protection from heart disease and guide future studies to determine how physiologic conditions (e.g. aging, obesity, diabetes) and pharmacologic interventions (e.g. contraceptives) affect these premenopausal protective factors.